Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." lontophoretic devices have been known since the early 1900's. British patent specification No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of the British patent specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activity.
More recently, a number of United States patents have issued in the electrolytic transdermal delivery field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Pat. No. 3,991,755 issued to Vernon et al., U.S. Pat. No. 4,141,359 issued to Jacobsen et al., U.S. Pat. No. 4,398,545 issued to Wilson, and U.S. Pat. No. 4,250,878 issued to Jacobsen disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is then collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged (i.e., a cation), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e. an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anode can deliver a positively charged ionic substance into the body while the cathode can deliver a negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Transdermal delivery of neutral compounds by the phenomenon of electroosmosis is described by Hermann Rein in Zeitschrift fur Biologie, Bd. 8 1, pp 125-140 (1924) and the transdermal delivery of non-ionic polypeptides by the phenomenon of electroosmosis is described in Sibalis et al., U.S. Pat. Nos. 4,878,892 and 4,940,456. Electroosmosis is the transdermal flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode. Similarly, electrophoresis is the transdermal flux of both the solute and the liquid solvent in an electric field. As used herein, the terms "electrotransport" and "electrolytic transdermal delivery" encompass both the delivery of charged ions as well as the delivery of uncharged molecules by the associated phenomenons of iontophoresis, electroosmosis, and electrophoresis.
Electrotransport delivery devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of ionized or ionizable agents include a pouch or cavity as described in the previously mentioned Jacobsen, U.S. Pat. No. 4,250,878, a porous sponge or pad as disclosed in Jacobsen et al., U.S. Pat. No. 4,141,359, or a preformed gel body as described in Webster, U.S. Pat. No. 4,383,529, and Ariura et al., U.S. Pat. No. 4,474,570. Such drug reservoirs are electrically connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired agents.
Electrotransport delivery devices which are attachable at a skin surface and rely on electrolyte fluids to establish electrical contact with such skin surfaces can be divided into at least two categories. The first category includes those devices which are prepackaged with the liquid electrolyte contained in the electrode receptacle. The second type of device uses dry-state electrodes whose receptacles or reservoirs are customarily filled with liquid drug/electrolyte immediately prior to application to the body. With both types of devices, the user currently experiences numerous problems which make their use both inconvenient and problematic.
With respect to the prefilled device, storage is a major concern. Many drugs have poor stability when in solution. Accordingly, the shelf life of prefilled iontophoretic drug delivery devices with such drug solutions is unacceptably short. Corrosion of the electrodes and other electrical components is also a potential problem with prefilled devices. For example, the return electrode assembly will usually contain an electrolyte salt such as sodium chloride which over time can cause corrosion of metallic and other electrically conductive materials in the electrode assembly. Leakage is another serious problem with prefilled iontophoretic drug delivery devices. Leakage of drug or electrolyte from the electrode receptacle can result in an inoperative or defective state. Furthermore, such prefilled devices are difficult to apply because the protective seal which covers the electrode opening and retains the fluid within the receptacle cavity must be removed prior to application on the skin. After removal of this protective seal, spillage often occurs in attempting to place the electrode on the skin. Such spillage impairs the desired adhesive contact of the electrode to the skin and also voids a portion of the receptacle cavity. The consequent loss of drug or electrolyte fluid tends to disrupt electrical contact with the electrode plate contained therein and otherwise disrupts the preferred uniform potential gradient to be applied.
Although dry-state electrodes have numerous advantages in ease of storage, several problems remain. For example, the drug and electrolyte receptacles of such a device are conventionally filled through an opening prior to application of the device to the patient's skin. Therefore, the same problem of spillage and loss of drug or electrolyte upon application occurs as with the pre-filled electrode.
Frequently, such electrodes are not well structured to develop the proper uniform current flow required in iontophoresis applications. Such nonuniform current flow may result from the occurrence of air pockets within the receptacle cavity at the skin surface. Such effects are particularly troublesome in electrolytic transdermal delivery applications, where a nonuniform current distribution may result in excessive skin irritation or "burning".
Hydrogels have been particularly favored for use as the drug reservoir matrix and electrolyte reservoir matrix in electrotransport delivery devices, in part due to their high equilibrium water content and their ability to absorb water from the body. In addition, hydrogels tend to have good biocompatibility with the skin and with mucosal membranes. However, since many drugs and certain electrode components are unstable in the presence of water, electrotransport drug delivery devices having a drug reservoir formed of a prehydrated hydrogel may also have unacceptably short shelf life. In particular, certain therapeutic agents have a limited shelf life at ambient temperature in an aqueous environment. Notable examples are insulin and prostaglandin sodium salt (PGE.sub.1).
One proposed solution to the drug stability problem is to use hydrophilic polymer drug and electrolyte reservoirs which are in a substantially dry or anhydrous state, i.e. in a non-hydrated condition. The drug and/or electrolyte can be dry blended with the hydrophilic polymer and then cast or extruded to form a non-hydrated, though hydratable, drug or electrolyte containing reservoir. Alternative methods also involve the evaporation of water and/or solvent from solution or emulsion polymers to form a dry polymer film. This process is energy intensive, however, and requires a large capital investment for equipment.
In addition, the prior art non-hydrated hydrophilic polymer components must first absorb sufficient quantities of water from the body before the device can operate to deliver drug. This delay makes many devices unsuited for their intended purpose. For example, when using an iontophoretic delivery device to apply a local anesthetic in preparation for a minor surgery (e.g. surgical removal of a mole), the surgeon and the patient must wait until the drug and electrolyte reservoirs of the delivery device become sufficiently hydrated before the anesthetic is delivered in sufficient quantities to induce anesthesia. Similar delays are encountered with other drugs.
In response to these difficulties, Konno et al., in U.S. Pat. No. 4,842,577, disclose in FIG. 4 an electrotransport device having a substantially non-hydrated drug containing layer or membrane filter and a separate water reservoir which is initially sealed, using a foil sheet, from the drug containing portions of the electrode. Unfortunately, this electrode design is not only difficult to manufacture but also is subject to severe handling restriction. In particular, there is a tendency for the foil seal to be inadvertently broken during manufacture, packaging, and handling of the electrode. This can have particularly drastic consequences especially when the seal is broken during manufacture of the device. Once the seal is broken, water is wicked into the drug-containing reservoir which can cause degradation of the drug and/or other components before the device is ever used.
Hydratable iontophoretic devices are known in the electrotransport art as disclosed in U.S. Pat. Nos. 5,158,537, 5,310,404, and 5,385,543, which are hereby incorporated in their entirety by reference. The reservoirs of these devices are preferably composed, at least in part, of a hydrophilic, natural or synthetic polymer material. Reservoir materials including low-substituted hydroxy propyl cellulose and hydrogels such as polyhydroxyethyl methacrylate are disclosed. The reservoir matrix may also include a hydrophobic polymer such as polyurethanes in order to enhance lamination of the reservoir to adjacent layers. Preferred hydroxypropyl cellulose and hydrophilic polyurethane compositions are not disclosed.
Additionally, WO 92/20324 discloses polyurethane hydrogel compositions for iontophoretic drug delivery. These polyurethane hydrogel compositions are prepared by dissolving an isocyanate-capped oxyalkylene-based polymer in a first solvent which comprises an anhydrous aprotic organic solvent to give a prepolymer solution. The prepolymer solution is then mixed with a second solvent which comprises water and optionally a water-miscible organic solvent to give a hydrogel forming mixture, which is then allowed to cure to give a hydrogel matrix. The hydrogels may alternately be prepared by mixing the isocyanate-capped oxyalkylene-based prepolymer in a total solvent comprising water and a water-miscible organic solvent to give the hydrogel forming mixture. Additional hydratable drug reservoirs for iontophoretic drug delivery devices are disclosed in U.S. Pat. Nos. 5,087,242 and 5,328,455, which are hereby incorporated in their entirety by reference.
The hydrophilic polymer components of the hydratable reservoir materials of the prior art typically require an extensive cure step to process the polymers which typically involves high temperatures. Heat sensitive drugs and/or excipients can not be processed at such high temperatures without degradation. Furthermore, such processing requires additional dispensing, casting and/or curing equipment.
Another disadvantage of using non-hydrated hydrophilic polymer components is that they have a tendency to delaminate from other parts of the electrode assembly during hydration. For example, when utilizing a drug reservoir matrix or an electrolyte reservoir matrix composed of a hydrophilic polymer, the matrix begins to swell as it absorbs water from the skin. In the case of hydrogels, the swelling is quite pronounced. Typically, the drug or electrolyte reservoir is in either direct contact, or contact through a thin layer of an ionically conductive adhesive, with an electrode. Typically, the electrode is composed of metal (e.g., a metal foil or a thin layer of metal deposited on a backing layer) or a hydrophobic polymer containing a conductive filler (e.g., a hydrophobic polymer loaded with carbon fibers and/or metal particles). Unlike the hydrophilic drug and electrolyte reservoirs, the electrodes do not absorb water and do not swell. The different swelling properties of the hydrophilic reservoirs and the electrodes results in shearing along their contact surfaces. In severe cases, the shearing can result in the complete loss of electrical contact between the electrode and the drug/electrolyte reservoir resulting in an inoperable device.
Thus, there remains a need for an easily manufacturable, anhydrous drug reservoir with an extended shelf life that can be manufactured at lower temperatures and which rapidly imbibes water and/or drug solution with good water retention and stability.